The N-methyl-D-aspartate Receptor (NMDA-R) is an ionotropic glutamate receptor with numerous well-docu- mented activities in neurons. Neuronal NMDA-R is a target for therapeutics development in Depression and Alzheimer's Disease. We have demonstrated that the NMDA-R is expressed by Schwann cells (SCs) and functions as an independent SC-signaling receptor for glutamate and as an essential co-receptor for LDL Re- ceptor-related Protein-1 (LRP1). We hypothesize that SC NMDA-R may have substantial effects on the res- ponse to PNS injury and chronic neuropathic pain. The major goal of this research project is to test this hypo- thesis. PNS injury activates a programmed response in SCs that facilitates clearance of damaged tissue, re- cruitment of inflammatory cells, and axonal regeneration so that normal nerve function is restored. These changes in SC activity are driven by cell-signaling factors such as c-Jun and alterations in the SC mRNA trans- criptome. Abnormalities in the SC response may result in neuropathic pain, a condition that afflicts millions of people and for which insufficient therapies are available. Our laboratories have shown that the transmembrane cell-signaling receptor, LDL Receptor-related Protein (LRP1), is expressed by SCs and essential for a normal SC response to PNS injury. When LRP1 is deleted in SCs in mice, multiple abnormalities in the response to PNS injury are observed, including exacerbated and sustained neuropathic pain. LRP1-signaling requires co- receptors and we have shown that in SCs, the NMDA-R is an essential LRP1 co-receptor. Neutralizing the ac- tivity of the NMDA-R in SCs blocks the effects of LRP1 on SC physiology, including its pro-survival activity and effects on SC migration. SC NMDA-R activates cell-signaling in response to glutamate, generating changes in SC phenotype that are similar to those observed when LRP1 is activated. If the activity of the NMDA-R is pharmacologically altered, for example by newly emerging drugs, the response to PNS injury may become abnormal, with increased risk of chronic neuropathic pain. To characterize SC NMDA-R, three specific aims are proposed. In Specific Aim 1, the activity of the NMDA-R as a regulator of SC signaling and the SC mRNA transcriptome will be characterized. Comparisons will be made to the changes observed when LRP1-signaling is activated in SCs and to documented changes in SC signaling and gene expression associated with acti- vation of the SC Repair Program. In Specific Aim 2, we will conditionally delete the gene that encodes the obligate NR1 NMDA-R subunit in SCs in mice and study the effects of this genetic change on the response to sciatic nerve injury. Nerve degeneration, cell-signaling in vivo, changes in the SC transcriptome, neuro-inflam- mation, and SC survival will be studied. In Specific Aim 3, we will test whether NMDA-R deficiency in SCs is associated with abnormalities in sensory or motor function, before and after nerve injury. This project will set the foundation for future work to assess how targeting neuronal NMDA-R with drugs intended to treat neuro- logical and psychiatric disorders may affect the response PNS injury and neuropathic pain.